You're listening to This Week in Cardiology from TheHeart.org, Medscape Cardiology. This podcast is intended for healthcare professionals only. Any views expressed are the presenter's own and do not necessarily reflect the views of WebMD or Medscape. Hi everyone, this is John Mandrola from TheHeart.org, Medscape Cardiology, and this is This Week in Cardiology for February 6, 2026. This week, some more problems with the prevent-risk equation, a new breakthrough in lipid-lowering therapy, an even more surprising benefit in stroke care, and some more thoughts on statins and preventive care of heart disease. So the first topic today is prevent-score problems. Now, in the old days, we used risk scores like Framingham and the pooled cohort equation, or PCE. These weren't perfect, but they were decent. Recently, key opinion leaders have come up with a new score called the PREVENT score, which is supposed to be better because it includes 30 to 39-year-olds, and that expands the age range. It adds heart failure, not just ASCVD. It removes race as a predictor, supposedly improving equity, and it adds optimal social determinants indexed and also includes kidney function. What's more, and I think perhaps the most valuable or beneficial thing with the PREVEN score is it's derived from more recent data and therefore better reflects modern cardiovascular epidemiology. Now, finally, let's not forget the point of these risk scores. The risk scores are used to guide treatment. Now, instead of treat everyone with, say, a blood pressure of 135 over 90, the risk score suggests treatment if a global 10-year risk reaches some set-out threshold. Now, I go on about this because of a very, very provocative paper published in Jack from the Kaiser Permanente group on using the prevent equations in young adults. This group assessed performance and algorithmic fairness of base and social determinant index augmented prevent equations in young adults age 30 to 39 and defined fairness as similar performance across racial and ethnic groups. They then did an exploratory analysis conducted among young adults age 20 to 29 years. Now, this was a big data study including 160,000 plus young adults with varying races and ethnic groups. The total incidence of cardiovascular disease was very low at 0.7%, which you'd expect because these are young people. The main finding was that the mean calibration found severe underprediction in non-Hispanic Black individuals. How bad? Well, the PREVENT score underestimated risk by 46% in this group. And of course, this is very important because it could lead to substantial undertreatment of black individuals with life-saving cholesterol and blood pressure meds. The authors assessed whether adding the social determinant index would improve calibration in black individuals, but it did not. so my comments it's ironic that the tool meant to prevent under treatment of young adults may actually cause under treatment of young black adults specifically the exact population with the highest premature cardiovascular disease burden i could use a simple example for instance of a non-hispanic black individual age 35 the blood pressure 135 over 85 on no meds prevent score predicts a 4% 10-year cardiovascular disease risk. The true risk might be 7% to 8%. So the clinician sees 4% and says, low risk, let's try lifestyle medications first, follow up in 6 months. But it probably ought to be this is moderate risk, indicating treatment is best to do now. Meanwhile, a Hispanic patient with identical values, prevent score predicts 4%, the true risk is about 4%, and that patient can get appropriate conservative management. Now, I've said this a blue million times on this podcast, but prediction is hard, especially about the future, like Yogi Berra said. Recently, I got kind of smashed on social media for suggesting a young woman needn't take statins because her overall risk was so low. Many suggested that we should treat regardless of overall risk, the thinking being that atherosclerosis is a slowly developing problem and the longer exposure to lower LDL cholesterol or lower blood pressure is going to be beneficial. But if you take that logic to its natural end, we may as well start in the teen years or even younger and then just treat everyone. There must be some happy medium where we use risk to guide therapy. Perhaps we don't have to hew so strongly to certain thresholds. For instance, there's nothing magic about this 7.5% risk threshold. What about 7.4% for instance? The thing that strikes me about this paper is that epidemiology clearly tells us that non-Hispanic black individuals have higher cardiovascular risk on average. And at least in this population studied, the PREVENT score led to underestimation of risk and this could lead to or would lead to significant under treatment if everybody just went by the risk scores. Now, the risk score that was designed to be race neutral performed worse on race, and it's kind of a head shaker. If I had a dollar for every instance in medicine where well-intentioned policy led to harm, like things like the healthcare readmission reductions program which penalized hospitals for high rates of readmissions may have actually led to higher mortality in heart failure Many years ago I visited the EP lab of Dr Dave Wilber in Chicago and I never forget it Over his stimulator, he had a sign that read in big letters, quote, resist the urge to help, and perhaps we need more of that in policy. All right, next topic is a new breakthrough in LDL cholesterol management with an oral PCSK9 inhibitor. New England Journal published the results of the Coral Reef Lipids trial of the oral PCSK9 drug enlicitide. The study was presented at AHA, but it's published this week, so we'll talk about it briefly. And I re-looked at the trial, and it's impressive. This was a big trial, about 3,000 patients who had an elevated LDL cholesterol, almost all of them on statins, and it was just enlistatide versus placebo. Primary endpoint of this trial was LDL cholesterol lowering, not cardiovascular outcomes. Enlistatide worked. It resulted in a about 55% reduction, placebo-resistant reduction in LDL cholesterol over the 52-week trial. there were no safety signals compared to placebo. And so my comments. This may be my briefest commentary on a trial ever, because this seems like a clear winner. The drug shreds non-HDL cholesterol, and it's on top of statins. The degree of reduction is similar to the injectable PCSK9 drugs, and it's more than benpedoic acid, more than azitamide, and more than incliceran. and a daily pill is always going to be better than a weekly injection. It's just easier. So I can't see how this drug doesn't help patients though. We need to remember this wasn't an outcomes trial, right? The LDL cholesterol is still a surrogate. It happens to be a very reliable surrogate for ASCVD, but it's still a surrogate. The authors tell us in the paper that Merck is sponsoring a large outcome trial called Coral Reef Outcomes Trial with a projected completion date of December of 2029. And of course, another major headwind for this drug in the U.S. will be cost because you can be sure that Merck will price the drug quite high. All right, speaking of wins, the next topic is a win for Factor XI inhibitor S-indoxian, and this is the Oceanic Stroke Trial. Now, a couple of years ago, the promise of Factor XI inhibition as a safer oral anticoagulant took a huge hit when the Oceanic AFib study of a Sundoxian versus Apixaban in patients with AF had to be stopped early because of higher stroke rates in the factor 11 arm. The factor 11 drug just didn't seem to have the anticoagulant efficacy that Apixaban had. At the time, in November of 23, the decision was made to continue the Oceanic Stroke study of a Sundoxian 50 milligrams daily versus placebo in patients with non-cardioembolic stroke or high-risk TIA. These are the type of stroke patients plan for antiplatelet therapy, either with single or dual antiplatelet therapy. Oceanic stroke had a primary endpoint of ischemic stroke and a primary safety endpoint of bleeding, along with many secondary endpoints. The trial results were just presented in New Orleans at the Stroke Congress. I don't think there's a paper yet, but I did find the slide deck thanks to Dr. Mike Gibson. on X. And I've attached that link in the show notes so you'll be able to see the slides. The inclusion criteria were adults within 72 hours of symptom onset. This was felt to be non-cardioembolic ischemic stroke with a NIHSS less than or equal to 15 or high-risk TIA. These patients had a history of atherosclerosis or evidence of plaque on imaging or non-lacooner stroke on imaging. They had a plan for antiplatelet therapy, single or dual. Now, of course, if the patient had AFib or another source of cardioemboli, they were not included in this study. This was a huge trial of over 6,000 patients per arm. Most of these patients had cardiovascular disease or substantial cardiovascular risk factors. The mean age was 68. Just under a third had interventional therapy with either endovascular or thrombolytic therapy for their acute stroke event. About two-thirds of the patients were on dual antiplatelet therapy. The main result was a 26% reduction in recurrent ischemic stroke over three years. 26% reduction. Hazard ratio 0.74, 95% conference interval 0.65 to 0.84 absolute risk reduction numbers it was 6.2% versus 8.4% over the time of the trial that's 2.2% absolute risk reduction NNT of 45 the main safety endpoint major bleeding was similar 1.9% versus 1.7% and importantly when they showed subgroup analysis it looked like this benefit, this 26% reduction, was pretty much preserved in all subgroups, including stroke subtypes. So, my comments. What else can you say about this? It's clearly a positive trial. There were no safety signals, and there was a clinically meaningful, statistically robust reduction in ischemic stroke. And in addition, the Kaplan-Meier curve seemed to be separating over time, meaning the NNT is getting less over time. And it's got to be considered a breakthrough because the only thing available for non-embolic stroke survivors has been antiplatelet drugs. Now we have a drug that reduces risk in addition to antiplatelets And importantly the S benefit was seen across all subgroups of stroke on the trial For instance, it was still beneficial in small vessel stroke and in cryptogenic stroke as well. Now, one question that I have, and perhaps you do too, is sunduxian was clearly inferior to apixaban and oceanic afib, and this was due to a lack of efficacy in stroke prevention. It just wasn't a good enough anticoagulant. Now, one theory of that was that the dosing was insufficient. But why did it have such a positive effect here in non-cardioembolic stroke? Perhaps the dose is enough for this group of patients, but not a pure AFib group. And it's curious to me. I mean, maybe you have ideas. This is a true question. Anyways, I do suspect this trial will be enough to gain approval for this indication of this new novel medication. All right, next topic today is a bit more on statin side effects. I mean, this topic never goes away. You have heard it a gazillion times. Statin have all kinds of side effects. Beyond muscle complaints to things like hepatic dysfunction, depression, cognition, sleep disturbance, acute kidney injury, renal failure, interstitial lung disease, and even pancreatitis. Now, these reports come from observational non-randomized studies, but they do get put into statin product labeling list, otherwise known as, quote, summaries of product characteristics. Well, the cholesterol treatment trialist, the CTT collaboration, have published a massive meta-analysis of 66 statin versus placebo trials in more than 123,000 patients, and they're looking specifically at 66 undesirable outcomes that have been attributed to statins and are on these summaries of product characteristics papers. The trials that they included were on atorvastatin, fluvastatin, pravastatin, resuvastatin, and simvastatin. And of course, because it's a CTT collaboration, they had individual patient-level data. They used a statistical technique to correct for multiple comparisons. it's sort of similar to but not exactly like the bonferroni correction method anyways what they found was no association of statin therapy with 62 of the 66 adverse events listed on the product summaries the four positive associations were number one transaminase elevation 0.3 percent per year versus 0.22 percent per year in placebo. Second, other LFT abnormalities like, say, for instance, Alkfos, 0.25 percent per year statin, 0.2 percent per year placebo. Third component, third adverse event, urine composition alterations, such as proteinuria, 0.21% per year versus 0.18% per year. And finally, edema, 1.38 versus 1.07%. So, my comments. Once again, we see that when you review blinded, randomized trials, adverse events with statins are minimal to none. The effects on liver biochemistry, urine composition, and edema are statistically significant, but I would argue not clinically meaningful. The authors conclude that the undesirable effects sections of statin product labels might overstate risks and then subsequently mislead clinicians and patients, and therefore they should be revised to better support, quote, informed evidence-based decision making. Now here, what pops into my mind, and I'm drawn to one of the most clever studies of this decade, really, honestly. The SAMSON trial, led by Dr. James Howard, this was an N-of-1 trial in patients with statin intolerance. So patients who felt like they were statin intolerance got enrolled in this trial, and these patients were randomized to alternating months of statin tablets, placebo tablets, and no tablets. The patients then kept their daily quality of life scores on an app. And the Samson authors found that the best months were the no tablet months. But, but, provocatively, these patients felt equally as bad whether they were taking a statin or a statin placebo. So the conclusion was that the act of taking a statin tablet caused adverse effects, but it didn't matter whether there was statin or nothing in the tablet. So it's a clear nocebo effect. And that leads me to being a neutral Martian on statins. I tell patients or anyone interested that these drugs reduce cardiovascular events in the subsequent five years by about 25% in relative terms. Higher risk people, of course, to a point, not dialysis patients or advanced heart failure people, but just generally higher cardiovascular risk people get more benefit because 25% of 15% is a bigger number than 25% of 5%. Now, whether that absolute risk reduction is worth taking a pill every day is 100% preference sensitive. I mean, it just depends. Some patients will do it, some patients won't do it. But what is clear to me is that there is an extremely low risk of adverse events. Now, the safety caveat here is that we don't know about potential long-term risk because trials don't go for 20 years. Dr Rod Hayward from Michigan and a link to his paper calls these unknown unknowns with statins And that caveat hints at the major weakness of this meta Namely, that when you meta-analyze trials, even with patient-level data available, you can only assess for short-term effects that have a high enough incidence to be detected. An adverse event that's rare is not going to be detected. or an adverse event that may accrue over 10 years. It's not going to be seen. That's not a knock on the CTT team. Rather, it's just a limitation of knowledge when you look at five-year trials. And this is why I think statins should be over-the-counter. People can do their risk calculation. They don't need doctors. They can assess their fear of coronary disease, and that's going to vary. And they can decide on whether the disutility or hassle of taking a pill is worth that reduction. Honestly, I just think people can decide this based on their risk reduction. Now, this discussion leads me to a new report in Jack on heart disease statistics. And I know, heart disease statistics doesn't sound exciting, but I want to point out one important thing from it. This was a monster paper led by Dr. Rishi Wadera from Beth Israel in Boston. But I would also say that the author list of this paper includes some of the best thinkers in cardiology today. And as I said, I'm not going to drone on on all the statistics of heart disease in 2026, but I want to highlight one important observation relative to the statin discussion I just mentioned, relative to cardiovascular prevention. Okay, here it is. The most notable statistic in this statistics paper was the dramatic reduction in coronary artery disease and acute MI-related mortality. Now, we all know that heart disease remains a leading killer. It is. But when you go into this JEC paper and you look at figure 24-26, it shows a steady and substantial decline in CAD-related mortality over the 10 to 20 years. And it's the same for AMI, even more significant drop in AMI. There's been a decreasing burden of AMI hospitalizations, as well as a decrease in AMI mortality rates. Figure 29 shows what we all see in our hospitals, and that is that it's increasingly uncommon for people to die from an acute MI. Now, to me, I think sometimes we forget this good news. You could tell me, John, CAD and AMI mortality are lower because of better prevention, so we should continue to push harder on it, like more statins. and it's hard for me to deny there is a component of causality in better preventative care but i'm not sure that it's the very large or the largest driver of these better outcomes for me smoking reduction is surely a large factor in better cardiovascular outcomes but even larger may be our interventional cardiologist and this podcast and i heap plenty of criticism for excessive revascularization in stable patients. But, but, I strongly believe that the acute treatment of AMI has been one of the greatest medical advances of our generation. Since door-to-balloon time became a thing and hospitals ramped up these care pathways and our profession together decided to make it standard to open occluded coronaries faster at all hours, heart disease has been greatly diminished. Not only has this decision improved survival, but it's greatly diminished the numbers of ICD-eligible heart fire patients. I, probably like any other EPs out there listening, it's rare for us to implant a primary prevention ICD due to ischemic cardiomyopathy. Why? Because infarcts rarely get left long enough to cause LV dysfunction. They get fixed. Patient gets a band-aid on their wrist and they go home and their EF is preserved. And I make this point about how amazing we are at reduction of AMI mortality and morbidity because the better a treatment of a disease gets, the less benefit there is to screening and early detection. I mean, there's no better example than breast cancer. As breast cancer treatment gets closer and closer to cure, the value of screening diminishes. And I think we're approaching something like that with acute MI and CAD. While I'm not advocating for telling people not to care about things like their blood pressure or BMI or their cholesterol, and I'm certainly not telling them to start smoking, it simply becomes harder and harder to contextualize a 10% versus an 8% 10-year risk of non-fatal MI. I mean, what does that really mean in the setting where AMIs are so well treated? Cardiology, especially interventional cardiology, has been good for humanity. And our progress isn't done, but the progress we have made does indeed affect decision-making regarding prevention and early detection. And so that's it for this week in cardiology. As always, I'm grateful that you listened. Thank you. And remember, if you like this podcast, please take the time. Give us a rating on the app you're using. Write us a review. These things help others find us. Until next week, from snowy, cold, super cold Kentucky, this is John Mandrola from the heart.org Medscape Cardiology. You're listening to This Week in Cardiology from the heart.org Medscape Cardiology. This podcast is intended for healthcare professionals only. Any views expressed are the presenter's own and do not necessarily reflect the views of WebMD or Medscape.
